Neuronal migration and connectivity of the cerebral cortex remain areas of great interest in developmental neurobiology and have been informed considerably through the analysis of animal models in which these processes are adversely affected. In this proposal, we will address the regulation of tangential migration and thalamocortical pathfinding through the analysis of a novel mutant mouse line in which both developmental processes are defective. Homozygous disconnected (disc) mutants display abnormal accumulations of tangentially migrating cortical interneurons at basolateral aspects of the cerebral cortex. In addition, thalamocortical connectivity is disrupted with thalamocortical axons defasciculating within the basal forebrain and being unable to ascend to their cortical target areas. Both defects maybe attributed to misspecification or other patterning defects within the basal forebrain. In this proposal, we will examine if these defects occur through cell-autonomous or non-cell autonomous mechanisms. Specifically, we will use organotypic cultures of brain slices in which we will transplant GFP-expressing cells from mutant or wild-type animals and observe the migration patterns of labeled cells. In addition, through a series of histological experiments using appropriate molecular markers, we will determine territorial identities within the basal forebrain of the mutant and compare them to the wild-type. Finally, we will use lypophilic dyes or transgenic marker expression to trace thalamocortical and corticofugal fibers in great detail with the aim to characterize their pathfinding defects. Identified commonalities in the way guidance of these fiber tracts is affected may provide clues as to the molecular and cellular mechanisms underlying the observed defects. This proposal utilizes the R21 grant mechanism with the aim to develop a body of data on which a hypothesis driven research program can be based. Understanding the exact nature of the phenotypic alterations characterizing affected disc mice will allow us to pursue the analysis of essential and possibly interconnected molecular pathways that are crucial for the regulation of tangential migration and thalamocortical connectivity. ) PUBLIC HEALTH RELEVANCE: Neurological disorders, like epilepsy can be the result of incorrect distribution and/or connectivity of neurons within the cerebral cortex. During development Wdfy3 regulates migration of cortical interneurons and the connections of the thalamus to the cerebral cortex making it a possible diagnostic or therapeutic target. )